CN114425051A - Application of lipoic acid in preparation of medicine for treating sepsis and/or septic shock - Google Patents
Application of lipoic acid in preparation of medicine for treating sepsis and/or septic shock Download PDFInfo
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- CN114425051A CN114425051A CN202210213789.3A CN202210213789A CN114425051A CN 114425051 A CN114425051 A CN 114425051A CN 202210213789 A CN202210213789 A CN 202210213789A CN 114425051 A CN114425051 A CN 114425051A
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- 229960002663 thioctic acid Drugs 0.000 title claims abstract description 48
- 239000003814 drug Substances 0.000 title claims abstract description 36
- 206010040047 Sepsis Diseases 0.000 title claims abstract description 31
- 206010040070 Septic Shock Diseases 0.000 title claims abstract description 13
- 230000036303 septic shock Effects 0.000 title claims abstract description 13
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Heart & Thoracic Surgery (AREA)
- Oncology (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of biological medicines, and provides application of lipoic acid in preparation of a medicine for treating sepsis and/or septic shock. The oxidative stress is an important mechanism for the pathogenesis of the sepsis, and the inhibition of the oxidative stress can effectively improve the oxidative stress in sepsis animal models and clinical tests of sepsis patients. Lipoic acid and metabolites thereof are natural biological antioxidants in vivo, and inhibit excessive inflammation in vivo by capturing free radicals in vivo, thereby protecting organ functions, reducing sepsis fatality rate, and improving patient prognosis.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of lipoic acid in preparation of a medicine for treating sepsis and/or septic shock.
Background
Sepsis (Sepsis) is organ dysfunction which is caused by the maladjustment of the body response to infection and endangers life, and Septic shock (Septic shock) refers to severe circulatory disorder and cell metabolic disorder which are caused by the combination of Sepsis and is a serious complication of critical patients such as infection, fever/trauma, shock and the like.
At present, sepsis has no specific medicine, and the intervention aiming at the pathophysiology mechanism of sepsis is more important, so that the sepsis is the key for improving the survival rate of patients. Sepsis, a clinical syndrome, is at the heart of Systemic Inflammatory Response Syndrome (SIRS), whose pathophysiological mechanisms involve multiple levels of molecules, cells and organs.
Previous researches show that, as an essential nutrient for endogenous antioxidation, high-dose vitamin C can relieve oxidative stress and inflammation, improve vasopressin synthesis, enhance immune cell function, improve intravascular function and apparent immune modification, and enhance antibacterial defense capability. The mechanisms by which vitamin C reduces the level of oxidative stress to protect organ function are currently known to include: inhibition of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase and activation of inducible Nitric Oxide (NO) synthase, increased tetrahydrobiopterin (FH4), prevention of oxidative phosphorylation uncoupling, reduction of superoxide and peroxynitrite formation, and direct superoxide elimination. Vitamin C can protect endothelial barrier by maintaining phosphorylation of cycloguanylate phosphatase and blocking protein, prevent apoptosis, recover reaction of blood vessel to vasoconstrictor, reduce application time of vasoactive medicine for septic shock patient, effectively prevent progressive organ dysfunction, and reduce patient mortality. Vitamin C also reduces platelet aggregation expressed by surface P-selectin, preventing oxidative damage to phagocytes. Several clinical trials have demonstrated the safety of vitamin C, and two recent studies have shown promising data for mortality improvement and hospital length reduction (see [ Fowler AA,3rd, SyedeAA, Knowlson S, Scultorope R, Farthing D, DeWilde C, Farthing CA, Larus TL, Martin E, Brophy DF et al: Phase I safety trial of intragenic ascorbic acid in patients with segment psis. J TranslMed 2014,12:32 ] and [ see
H,Chalker E:Vitamin C Can Shorten the Length of Stay in the ICU:A Meta-Analysis.Nutrients 2019,11(4).】)。
Vitamin C, however, still has limitations as a therapeutic agent for sepsis. First, the effect of single vitamin C in the treatment of sepsis is not exact, and many clinical studies have used antioxidant cocktail therapy. Second, the need for large intravenous doses of vitamin C (minimum 3g/d, 30 times the recommended dose) to restore normal serum values can lead to metabolic acidosis, interference with known and other unknown adverse outcomes such as blood glucose monitoring. Current guidelines for sepsis therapy also do not support the administration of high doses of vitamin C to critically ill patients.
The lipoic acid is a B-group vitamin and is a coenzyme of a pyruvate dehydrogenase system and an alpha-ketoglutarate dehydrogenase system, and in vitro experiments show that the lipoic acid can reduce lipid oxidation of nervous tissues, inhibit protein glycosylation and inhibit aldose reductase. In vivo, lipoic acid has antioxidant effect, and participates in the recycling of antioxidants such as glutathione and coenzyme Q10. Lipoic acid has the functions of capturing and eliminating free radicals, chelating metal ions, and regenerating (reducing) other antioxidants as an antioxidant. The lipoic acid has fat-soluble and water-soluble properties, has stronger oxidation resistance than vitamin C (only water-soluble) and vitamin E (only fat-soluble), and has the super-strong function of cleaning oxygen free radicals. Animal studies indicate that lipoic acid exerts a potent antioxidant effect in vivo. Lipoic acid is widely used in clinic as a biological antioxidant, especially in the treatment of diabetes. Meanwhile, it is also used for treating senile cardiovascular diseases, cognitive disorders, neuromuscular diseases and the like, and is a regulator of some inflammatory signal pathways. Lipoic acid also inhibits lipid peroxidation in the brain, and studies show that lipoic acid is helpful for improving the curative effect of patients suffering from acute cerebral infarction. The lipoic acid has good prevention and treatment effects on various cardiovascular diseases such as atherosclerosis and the like, and also has an inhibition effect on the inflammatory response of viral myocarditis.
However, there is currently no report of the use of lipoic acid for the treatment of sepsis and/or septic shock.
Disclosure of Invention
In view of the above, the present invention aims to provide an application of lipoic acid in preparation of a medicament for treating sepsis and/or septic shock.
The invention provides application of lipoic acid in preparation of a medicine for treating sepsis and/or septic shock.
Preferably, the dosage form of the medicament comprises an injection.
Preferably, the lipoic acid comprises lipoic acid injection.
Preferably, the lipoic acid injection is purchased from Yabao pharmaceutical industry group, Inc.
Preferably, the concentration of the lipoic acid injection in the medicine is 300mg/12 mL.
Preferably, the concentration of the lipoic acid injection in the medicine is 12mg/5 mL.
Preferably, the medicament also comprises pharmaceutically acceptable auxiliary materials; the auxiliary material comprises normal saline.
Preferably, the lipoic acid is the only active ingredient in the medicament.
Preferably, the medicament comprises an adult medicament.
The invention provides application of lipoic acid in preparation of a medicine for treating sepsis and/or septic shock. Oxidative stress is an important mechanism for Sepsis pathogenesis, and inhibition of oxidative stress can effectively improve oxidative stress in Sepsis animal models and clinical tests of Sepsis patients. Lipoic acid and metabolites thereof are natural biological antioxidants in vivo, and inhibit excessive inflammation in vivo by capturing free radicals in vivo, thereby protecting organ functions, reducing the mortality of Sepsis, and improving patient prognosis.
Detailed Description
The invention provides application of lipoic acid in preparation of a medicine for treating sepsis and/or septic shock.
In the present invention, the dosage form of the drug preferably includes an injection.
In the present invention, the lipoic acid preferably comprises lipoic acid injection. In the present invention, the lipoic acid injection is preferably purchased from 300 mg/piece of Yabao pharmaceutical industry group, Inc., and the active ingredient is lipoic acid 300mg, 12mL per piece.
In the present invention, the medicament preferably further comprises pharmaceutically acceptable excipients. In the present invention, the supplementary material preferably includes physiological saline.
In the present invention, the lipoic acid is preferably the only active ingredient in the drug.
In the present invention, the drug preferably includes an adult drug.
In the present invention, the drug is preferably prepared by the following method: mixing the lipoic acid injection and normal saline.
In the invention, the using method of the medicine is preferably intravenous drip, and preferably, the lipoic acid injection is added into physiological saline, wrapped by aluminum platinum paper in the dark and subjected to intravenous drip; the time of the intravenous drip is preferably 30min, the frequency of the intravenous drip is 1 time per day, the dosage of the lipoic acid injection liquid of each intravenous drip is preferably 600mg, and the dosage of the physiological saline is preferably 250 mL; the time of use of the drug is preferably 7 days.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention.
Example 1
1. Sample size estimation
In the study, 28-day all-cause mortality is taken as a main curative effect index, through large-scale ICU epidemiological survey, the 28-day all-cause mortality of a control group is 38.2%, the Relative risk reduction value (RRR) of a lipoic acid injection treatment group Relative to the control group is about 0.33, the 28-day all-cause mortality of the treatment group is expected to be 22.9%, a single-side test is adopted, α is 0.025, β is 0.2 (efficacy is 80%), a cut-off value Δ is 0, a high-efficiency test (low-quality) is adopted, and the treatment group and the control group are tested according to the following formula 1:1 proportion of cases, 160 samples in each group, and 352 samples in each group, which is 176 samples in the treatment group and the control group, with the shedding factor considered, increased by about 10%.
2. Case grouping
352 subjects were enrolled in the study. Subjects were from the reporting unit and the cooperative unit ICU ward and had been diagnosed as Sepsis patients according to the Sepsis-3 standard and were screened. Subjects meeting the criteria for inclusion will be randomly assigned to the lipoic acid group and placebo group at a 1:1 ratio and will have corresponding treatment and visit observations. The lipoic acid group was treated with lipoic acid injection.
Placebo group: 1/2 for treatment on a regular schedule with placebo administered in a proportion of the total population in the group; lipoic acid group: 1/2 is used in combination with conventional therapy and thioctic acid therapy.
3. Randomization
To minimize the differences in patient origin between hospitals, the study center performed a computer-generated block randomization (block size 8). The randomization method and block size were not blinded before all data analysis was completed. The clinician enrolled in the patient is not involved in collecting the data. The enrolled patients were randomly assigned to each hospital by the randomization center at a 1:1 ratio by phone verification, with 4 patients in each group receiving medication (lipoic acid group) and 4 other patients as controls (placebo group). The patient assignment sequence is hidden from the researcher. To prevent prior knowledge of treatment assignment and disruption of assignment sequence, test entry forms in Case Report Form (CRF) were filled out and informed consent was signed before the unique participating number and assignment group were uncovered, after which this unique number had to be changed and deleted.
4. Research center
The primary definition is 9 centers, namely a Min hospital in Maoming city, a Min hospital in Guangdong province, an affiliated hospital of Guangdong medical university, an affiliated second hospital of Guangzhou medical university, a Min hospital in Zhanjiang center, a Min center hospital in Huizhou city, a Min hospital in Zhongshan province, a Min hospital in Huizhou city and a Min hospital in Yunfo city.
5. Research drug
600mg thioctic acid injection (Yabao pharmaceutical industry group Co., Ltd.) was added to 250ml of physiological saline, and the mixture was covered with an aluminum-platinum paper and applied by intravenous drip for about 30min 1 time per day for 7 days.
Period of treatment
Both groups were treated routinely according to Sepsis-3 guidelines established by the American society for severe medical Science (SCCM)/European society for critical illness medical (ESICM). Subjects were divided into placebo or lipoic acid groups for treatment according to the corresponding treatment regimen. Wherein placebo group: 250ml of placebo physiological saline is added, and the mixture is wrapped by aluminum platinum paper to be protected from light and is subjected to intravenous drip for about 30 minutes; the thioctic acid group is prepared by treating 600mg thioctic acid injection (Yabao pharmaceutical industry group Co., Ltd.) with thioctic acid injection on the basis of conventional treatment, adding into 250ml normal saline, wrapping with aluminum platinum paper, keeping out of the sun, and performing intravenous drip for about 30 minutes.
The initial test results of 11 people in the lipoic acid group and 10 people in the control group are shown in the table 1, and the results in the table 1 show that the inflammation level, the death rate and the incidence rate of acute renal function injury of the lipoic acid group patients are reduced compared with those of the placebo group.
TABLE 1 Tinocinic acid injection and control group associations
Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and the embodiments are within the scope of the present invention.
Claims (8)
1. Use of lipoic acid in the manufacture of a medicament for the treatment of sepsis and/or septic shock.
2. The use of claim 1, wherein the pharmaceutical dosage form comprises an injectable formulation.
3. The use of claim 2, wherein said lipoic acid comprises lipoic acid injection.
4. The use according to claim 3, wherein the lipoic acid injection is available from Artocarpus heterophyllus group GmbH.
5. The use of claim 3 or 4, wherein the concentration of lipoic acid injection in the medicament is 300mg/12 mL.
6. The use according to any one of claims 1 to 4, wherein the medicament further comprises pharmaceutically acceptable excipients; the auxiliary material comprises normal saline.
7. The use according to any one of claims 1 to 4, wherein lipoic acid is the only active ingredient in the medicament.
8. The use of any one of claims 1 to 4, wherein the medicament comprises an adult medicament.
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| CN1207683A (en) * | 1995-12-14 | 1999-02-10 | M·B·巴拉佐夫斯基 | Cytokine and Hemopoietic factor endogenous production enhancer and method of use thereof |
| CN1802102A (en) * | 2003-02-05 | 2006-07-12 | 努特里奇亚有限公司 | Enteral composition for the prevention and/or treatment of sepsis |
| CN1882348A (en) * | 2003-09-19 | 2006-12-20 | 努特里奇亚有限公司 | Carbohydrate composition and its use for the preparation of a medicament for treating or preventing pulmonary inflammation or acute respiration distress syndrome |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1207683A (en) * | 1995-12-14 | 1999-02-10 | M·B·巴拉佐夫斯基 | Cytokine and Hemopoietic factor endogenous production enhancer and method of use thereof |
| US6165979A (en) * | 1995-12-14 | 2000-12-26 | Novelos Therapeutics, Inc. | Cytokine and hemopoietic factor endogenous production enhancer and methods of use thereof |
| CN1802102A (en) * | 2003-02-05 | 2006-07-12 | 努特里奇亚有限公司 | Enteral composition for the prevention and/or treatment of sepsis |
| CN1882348A (en) * | 2003-09-19 | 2006-12-20 | 努特里奇亚有限公司 | Carbohydrate composition and its use for the preparation of a medicament for treating or preventing pulmonary inflammation or acute respiration distress syndrome |
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Application publication date: 20220503 |